1. Field of the Invention
The present invention relates to a process for the preparation of optically-active N-(D-.alpha.-alkyl-.beta.-mercaptopropionyl)-L-prolines.
2. Description of the Related Art
N-(D-.alpha.-methyl-.beta.-mercaptopropionyl)-L-proline (common name: Captopril) represented by the following formula (IV): ##STR4## have been found extremely useful as hypotensive agents because of their strong inhibitory effect against the angiotensin-converting enzyme and marked hypotensive effect based on this enzyme inhibition (Biochemistry, 16, 5487 (1977)).
As a process for preparing such N-(D-.alpha.-alkyl-.beta.-mercaptopropionyl)-L-prolines, it has been known to react optically-active D-.alpha.-alkyl-.beta.-acylthiopropionic acid halides as starting materials with L-proline in an organic solvent or an aqueous medium, to isolate resulting N-(D-.alpha.-alkyl-.beta.-acylthiopropionyl)-L-prolines and then to subject the thus-isolated compounds to deacylation, thereby yielding the N-(D-.alpha.-alkyl-.beta.-mercaptopropionyl)-L-prolines as desired. Reactions in an organic solvent have been reported in Japanese Patent Laid-open No. 40676/1980, while those in an aqueous medium in Japanese Patent Laid-open No. 18985/1981.
The acid halides, starting materials, however, are unstable to water. Unless some special care is exercised for the reactions (amidation) between the acid halides and L-proline as in the present invention, hydrolysis of the acid halides occurs, resulting in the byproduction of D-.alpha.-alkyl-.beta.-acylthiopropionic acids, which are hydrolysates of the acid halides. Therefore, organic solvents inert to the acid halides, such as halogenated hydrocarbons and tetrahydrofuran, are ordinarily used as reaction media for the amidation. Although the use of such organic solvents can prevent the hydrolysis of the acid halides, there is the problem that L-proline is only sparingly soluble in such organic solvents. It has, therefore, been inevitable to conduct the amidation by suspending L-proline in a solid form at the sacrifice of the reaction efficiency or to follow the cumbersome process that the reactions are conducted after converting L-proline to an ester soluble in such organic solvents.
In the above amidation, a condensation agent for deacidification is required for the scavenging of the hydrogen halide given off from the acid halides. The use of an organic solvent as a reaction medium, however, does not allow to employ an economical alkali metal hydroxide such as sodium hydroxide. It has, therefore, been inevitable to employ an expensive organic amine such as N,N-dimethylaniline from the viewpoint of its solubility in an organic solvent. Such an organic amine should be separated and recovered from the amides, the reaction products. The separation and recovery of the organic amine are, however, more difficult than those of the alkali metal hydroxide, leading to the problem that the unrecovered organic amine tends to mix in the products as an impurity.
Schotten-Baumann reactions between the acid halides and L-proline, when conducted in an aqueous medium, are not accompanied by such a problem as encountered in the reactions in an organic solvent, but hydrolysis of the acid halides arises as a new problem. In the process specifically described in Japanese Patent Laid-open No. 18958/1981, the acid halides are dissolved in an organic solvent such as tetrahydrofuran and the resulting solutions are added to an aqueous solution of L-proline to avoid the hydrolysis.
Such processes, however, use an organic solvent, thereby involving the problem of the need for complex post-treatment to separate and remove the organic solvent from the aqueous solutions of the resultant reaction products. In addition, various byproducts such as hydrolysates of the acid halide and reaction products produced by further reaction of Schotten-Baumann reaction products generally tend to occur in Schotten-Baumann reactions. If a Schotten-Baumann reaction product having an acyl group is subjected to deacylation in order to obtain a final product having a mercapto group as in the present invention, the purification of the final product will be difficult unless such byproducts are removed beforehand, because the final product is water-soluble. There has, hence, been no way other than following the steps that the Schotten-Baumann reaction product is once isolated and purified and then subjected to deacylation and the thus-obtained deacylation product is purified.